EP2120561A1 - Compositions pour traiter des biofilms, et procédés pour leur utilisation - Google Patents

Compositions pour traiter des biofilms, et procédés pour leur utilisation

Info

Publication number
EP2120561A1
EP2120561A1 EP08730165A EP08730165A EP2120561A1 EP 2120561 A1 EP2120561 A1 EP 2120561A1 EP 08730165 A EP08730165 A EP 08730165A EP 08730165 A EP08730165 A EP 08730165A EP 2120561 A1 EP2120561 A1 EP 2120561A1
Authority
EP
European Patent Office
Prior art keywords
poloxamer
composition
antimicrobial agent
surface active
dressing
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP08730165A
Other languages
German (de)
English (en)
Other versions
EP2120561A4 (fr
Inventor
George Rodeheaver
Adam Katz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
PLUROGEN THERAPEUTICS Inc
Original Assignee
PLUROGEN THERAPEUTICS Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by PLUROGEN THERAPEUTICS Inc filed Critical PLUROGEN THERAPEUTICS Inc
Priority to EP16202292.5A priority Critical patent/EP3170396A1/fr
Publication of EP2120561A1 publication Critical patent/EP2120561A1/fr
Publication of EP2120561A4 publication Critical patent/EP2120561A4/fr
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/44—Medicaments
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/54—1,3-Diazines; Hydrogenated 1,3-diazines
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N59/00—Biocides, pest repellants or attractants, or plant growth regulators containing elements or inorganic compounds
    • A01N59/16—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A61F13/00051—Accessories for dressings
    • A61F13/00063—Accessories for dressings comprising medicaments or additives, e.g. odor control, PH control, debriding, antimicrobic
    • A—HUMAN NECESSITIES
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    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A61F13/02—Adhesive bandages or dressings
    • A61F13/0269—Tapes for dressing attachment
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
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    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/38—Silver; Compounds thereof
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/46—Deodorants or malodour counteractants, e.g. to inhibit the formation of ammonia or bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/48—Surfactants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0019—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
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    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • A61L26/0066—Medicaments; Biocides
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A61F2013/00361—Plasters
    • A61F2013/00544—Plasters form or structure
    • A61F2013/00621—Plasters form or structure cast
    • A61F2013/00638—Gel
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    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
    • A61L2300/104—Silver, e.g. silver sulfadiazine
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    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/204—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with nitrogen-containing functional groups, e.g. aminoxides, nitriles, guanidines
    • A—HUMAN NECESSITIES
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    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/216—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with other specific functional groups, e.g. aldehydes, ketones, phenols, quaternary phosphonium groups
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    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
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    • A61L2300/406—Antibiotics

Definitions

  • Bacteria and fungi form biofilms under certain conditions. When a group of bacteria or fungi accumulate on a surface and reach a particular cell density, they begin to secrete a polymeric substance that consists of polysaccharides, proteins and DN ⁇ and form a matrix in which the bacterial or fungal cells are entrenched.
  • the multi-cellular aggregates or bioiilms allow for individual bacterial or fungal cells or colonies of bacterial or fungal cells to exhibit coordinated behavior and confer upon the microorganism advantages including, for example, resistance to antibiotics and host immune systems.
  • biofilms arc structured to allow respiration and fluid and nutrient exchange while preventing access of host immune cells such as phagocytes and preventing inhibitory or lytic concentrations of antimicrobials from reaching the microorganisms.
  • host immune cells such as phagocytes
  • inhibitory or lytic concentrations of antimicrobials from reaching the microorganisms.
  • Biofilm formation appears to be governed by secretion and detection of autoinducer molecules in a process referred to as "quorum sensing.”
  • quorum sensing autoinducer molecules begin to accumulate in the area surrounding the microorganisms
  • the microorganisms begin to undergo a number of physiological changes which allow for formation of the extracellular biofilm.
  • the microorganisms may begin surface attachment, extracellular polymer production, biosurfactant production, sporulation, bioluminescence and secretion of nutrient sequesteration molecules and virulence factors among other effects resulting in biof ⁇ lm formation.
  • microorganisms in a biofilm are typically less susceptible to antibiotics, antimicrobials and biocides.
  • bacteria in a biofilm can be up to 4,000 times more resistant (i.e., less susceptible) than the same organism in a free-floating (planktonic) slate.
  • MIC minimum inhibitory concentration
  • MBEC minimum biofilm eradication concentration
  • Embodiments of the invention described herein are directed to a method for treating a microbial biofilm on a patient including the steps of contacting the microbial biofilm with a composition comprising a surface active agent and a sub-lethal amount of an antimicrobial agent.
  • the antimicrobial agent may be an antibacterial, antifungal, antiviral or combinations thereof, and in others, the antimicrobial agent may be furahadone, furazolium chloride, nifuradene, nifuratel, nifurfoline, nifurpirinol, nifurprazine, nifurtoino], nitrofurantoin, furazolidone, 2-(methoxymethyl)-5-nitrof ⁇ iran, nidroxyzone, nifuroximc, nifurazide, nitrofurazone, nystatin, polymyxin, silver sulfadiazine, nanocrystalline silver, ionic silver, honey, iodine, benzalkonium chloride, alcohol, hydrogen peroxide, chlorhexidine or combinations thereof.
  • a sub-lethal amount of an antimicrobial agent may be a standard therapeutically effective amount.
  • the antimicrobial agent may be silver sulfadiazine and the sub-lethal amount may be less than about 1% by weight of the composition, less than about 0.95% by weight of the composition, or less than about-0.75% by weight of the composition.
  • the surface active agent of embodiments may be a poloxamer, meroxapol, poloxaminc or combinations thereof.
  • the surface active agent may be a poloxamer 127, poloxamer 188, poloxamer 237, poloxamer 335, poloxamer 407 or combinations thereof, and in certain embodiments, the surface active agent may be poloxamer 188.
  • the step of contacting the microbial biofilm in various embodiments may include applying the composition to a wound.
  • the step of contacting the microbial biofilm may include administering the composition topically, and in particular embodiments, administering the composition topically may be selected from administering by hand, administering by an extruder, spray delivery, applying a dressing including the composition or combinations thereof.
  • the step of contacting the microbial biofilm may include contacting tissue from the patient that is outside the patient, and in still other embodiments, the step of contacting may include applying the composition to a dressing prior to applying the dressing to the patient.
  • the patient may be afflicted with an injury, and in certain embodiments, the injury may be a burn, abrasion, cut, scrape, denuding tissue injury or combinations thereof.
  • the patient may be afflicted with a chronic wound, and in particular embodiments, the chronic wound may be a venous ulcer, diabetic ulcer, arterial ulcer, pressure ulcer, radiation ulcer, traumatic wound, non-healing wound or combinations thereof.
  • Embodiments of the invention also include a method for preventing a microbial biofilm on a patient including the steps of administering a composition comprising a surface active agent and a sub-lethal amount of an antimicrobial agent to an injury.
  • the antimicrobial agent may be an antibacterial, antifungal, antiviral or combinations thereof, and in others, the antimicrobial agent may be furaltadone, furazolium chloride, nifuradene, nifuratel, nifurfoline, nifurpirinol, nifurprazinc, nifiirtoinol, nitrofurantoin, furazolidone, 2-(methoxymethyl)-5-nitrofuran, nidroxyzone, nifuroxime, nifurazide, nitrofurazone, nystatin, polymyxin, silver sulfadiazine, nanocrystallinc silver, ionic silver, honey, iodine, bcnzalkonium chloride, alcohol, hydrogen peroxide, chlorhexidine or combinations thereof.
  • the antimicrobial agent may be silver sulfadiazine and the sub-lethal amount may be less than about 1% by weight of the composition, less than about 0.95% by weight of the composition, or less than about 0.75% by weight of the composition.
  • the surface active agent of embodiments may be a poloxamer, meroxapol, poloxamine or combinations thereof.
  • the surface active agent may be a poloxamer 127, poloxamer 188, poloxamer 237, poloxamer 335, poloxamer 407 or combinations thereof, and in certain embodiments, the surface active agent may be poloxamer 188.
  • the step of contacting the microbial biofilm in various embodiments may include applying the composition to a wound.
  • the step of contacting the microbial biofilm may include administering the composition topically, and in particular embodiments, administering the composition topically may be selected from administering by hand, administering by an extruder, spray deliver)', applying a dressing including the composition or combinations thereof.
  • the step of contacting the microbial biofilm may include contacting tissue from the patient that is outside the patient, and in still other embodiments, the step of contacting may include applying the composition to a dressing prior to applying the dressing to the patient.
  • the composition may be administered while biofilm forming pathogens are in a planktonic state.
  • inventions include a method for treating or preventing a microbial biofilm in a patient including the steps of administering a first composition comprising a surface active agent to an injury wherein the first composition does not contain an antimicrobial agent and administering a second composition comprising a surface active agent and a sub-lethal amount of an antimicrobial agent to the injury.
  • the first composition may be administered before the second composition, and in some embodiments, the second composition may be applied to a dressing prior to its administration.
  • the antimicrobial agent of the second composition may be an antibacterial, an antifungal, an antiviral or a combination thereof, and in some embodiments, the antimicrobial agent of the second composition may be furaltadone, furazolium chloride, nifuradene, nifuratel, nifurfoline, nifurpirinol, nifurprazine, nifurtoinol, nitrofurantoin, furazolidone, 2-(raethoxymethyl)-5-nitrofuran, nidroxyzone, nifuroxime, nifurazide, nitrofurazone, nystatin, polymyxin, silver sulfadiazine silver salts, nanocrystalline silver, ionic silver, iodine, benzalkonium chloride, alcohol, hydrogen peroxide, chlorhexidinc or combinations thereof.
  • the antimicrobial agent may be silver sulfadiazine and the sub-lethal amount may be less than about 1% by weight of the composition, less than about 0.95% by weight of the composition, or less than about 0.75% by weight of the composition.
  • the surface active agents in the first and second composition of various embodiments may be surfactants.
  • the surface active agents in the first and second compositions may independently be poloxamcr 127, poloxamer 188, poloxamer 237, poloxamer 335, poloxamer 407 or combinations thereof.
  • the surface active agents in the first and second compositions may be the same, and in at least one embodiment, surface active agents in the first and second compositions may be poloxamcr 188.
  • Embodiments also include a composition for treating or preventing a microbial biofilm including a surface active agent and a sub-lethal amount of an antimicrobial agent.
  • the antimicrobial agent may be an antibacterial, antifungal, antiviral or combinations thereof, and in others, the antimicrobial agent may be furaltadone, furazolium chloride, nifuradene, nifuratel, rrifurfoline, nifurpirinol, nifurprazine, nifurtoinol, nitrofurantoin, furazolidone, 2-(methoxymethyl)-5-nitrofuran, nidroxyzone, nifuroxime, nifurazide, nitrofurazone, nystatin, polymyxin, silver sulfadiazine, nanocrystalline silver, ionic silver, honey, iodine, benzalkonium chloride, alcohol, hydrogen peroxide, chlorhexidine or combinations thereof.
  • a sub-lethal amount of an antimicrobial agent may a standard therapeutically effective amount.
  • the antimicrobial agent may be silver sulfadiazine and the sub-lethal amount may be less than about 1% by weight of the composition, less than about 0.95% by weight of the composition, or less than about 0.75% by weight of the composition.
  • the surface active agent of various embodiments may be a poloxamer, ineroxapol, poloxaminc or combinations thereof.
  • the poloxamer may be a poloxamer 101, poloxamcr 105, poloxamer 105 benzoate, poloxamer 108, poloxamer 122, poloxamer 123, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 182 dibcnzoate, poloxamer 183, poloxamcr 184, poloxamer 185, poloxamer 188, poloxamer 212, poloxamer 215, poloxamer 217, poloxamcr 231, poloxamer 234, poloxaraer 235, poloxamer 237, poloxamer 238, poloxamer 282, poloxamer 284, poloxamer 288, poloxamer 331, poloxamer 333, polox
  • the surface active agent is a copolymer selected from poloxamer 127, poloxamer 188, poloxamer 237, poloxamer 335, poloxamer 407 or combinations thereof.
  • the surface active agent may be poloxamer 188.
  • the mcroxapol may be a meroxapol 105, meroxapol 108, meroxapol 171, meroxapol 172, meroxapol 174, meroxapol 178, meroxapol 251, meroxapol 252, meroxapol 254, meroxapol 258, meroxapol 311, meroxapol 312, meroxapol 314 or combinations thereof.
  • the poloxamine may be a poloxamine 304, poloxaminc 504, poloxamine 701, poloxaminc 702, poloxamine 704, poloxamine 707, poloxamine 901 , poloxamine 904.
  • the composition may include one or more secondary active agents, and in others, the composition may include one or more additives.
  • the composition may further include a solvent.
  • Embodiments of the invention also include a dressing for treating or preventing a microbial biofilm including a first composition layer comprising a surface active agent wherein the first gel layer does not include an antimicrobial agent, a second composition layer comprising a surface active agent and a sub-lethal amount of an antimicrobial agent, and a dressing material supporting said first and second composition layers.
  • the second composition layer may be located between the first composition layer and the dressing material.
  • the antimicrobial agent may be an antibacterial, antifungal, antiviral or combinations thereof, and in others, the antimicrobial agent may be furaltadone, furazolium chloride, nifuradene, nifuratel, nifurfoline, nifurpirinol, nifurprazine, nilurtoinol, nitrofurantoin, furazolidone, 2-(methoxymethyl)-5-nitrofuran, nidroxyzone, nifuroxime, nifurazide, nitrofurazonc, nystatin, polymyxin, silver sulfadiazine, nanocrystalline silver, ionic silver, honey, iodine, benzalkonium chloride, alcohol, hydrogen peroxide, chlorhexidine or combinations thereof.
  • the antimicrobial agent may be silver sulfadiazine and the sub-lelhal amount may be less than about 1% by weight of the composition, less than about 0.95% by weight of the composition, or less than about 0.75% by weight of the composition.
  • the surface active agent of embodiments may be a poloxamer, meroxapol. poloxamine or combinations thereof.
  • the surface active agent may be a poloxamer 127, poloxamer 188, poloxamer 237, poloxamer 335, poloxamer 407 or combinations thereof, and in certain embodiments, the surface active agent may be poloxamer 188.
  • the surface active agent in the first and second compositions may be the same.
  • the dressing may further include a spacer material layer between said first and second composition layers.
  • the spacer material of such embodiments may fully or partially lose integrity upon application of the dressing to a patient.
  • the second composition layer may impregnate the dressing material.
  • inventions also include a method for preventing a microbial biof ⁇ lm on a patient including the steps of administering a composition including a surface active agent and a sub-lethal amount of an antimicrobial agent to a wound prior to infection.
  • Still other embodiments of the invention include a method for preventing a microbial biofilm on a patient including the steps of administering a composition including a surface active agent and a sub-lethal amount of an antimicrobial agent to a wound while biofilm forming bacteria are in a planktonic state.
  • Yet other embodiments of the invention include a method for preventing a microbial biofilm on a patient including the steps of administering a composition comprising a surface active agent and a sub-lethal amount of an antimicrobial agent to a wound prior to infection wherein the composition is administered within 10 hours of the injury.
  • Further embodiments of the invention include a method for treating or preventing a microbial biofilm on a patient including the steps of administering a composition comprising a surface active agent to a wound.
  • administering when used in conjunction with a therapeutic means to administer a therapeutic directly into or onto a target tissue or " to administer a therapeutic to a patient whereby the therapeutic positively impacts the tissue to which it is targeted.
  • administering a composition may be accomplished by injection, infusion, or by either method in combination with other known techniques. Such combination techniques include heating, radiation and ultrasound.
  • treating generally mean the exposure of a living organism to one or more physical, chemical or psychological entities or stimuli that may prevent, improve or ameliorate a diseased stale. These terms are also meant to encompass exposing an inanimate object (e.g., biomaterial) to physical or chemical entities or stimuli that may enhance the object's capacity to alter a disease process in living organisms which is contacted by the object.
  • an inanimate object e.g., biomaterial
  • treating a biomaterial may include applying a composition to a surface of a biomaterial to enhance resistance to biofilm development, dissolve an existing biof ⁇ lm and/or deliver a therapeutic to the biomaterials.
  • Biomaterial treatment may encompass treating an entry site for catheters in the body of a patient which allow access of the catheter to, lor example, blood vessels, body cavities, cerebrospinal space and the like.
  • indication' refers to a medical condition or symptoms associated with a medical condition, such as biofilm infection.
  • a medical condition such as biofilm infection.
  • redness and swelling of tissue surrounding an injury may be an indication of subject in a diseased state.
  • target refers to the material for which deactivation, rupture, disruption or destruction is desired.
  • infectious microorganisms or bioi ⁇ lrns may be considered undesirable material in an injured subject and may be a target for therapy.
  • tissue refers to any aggregation of similarly specialized cells which are united in the performance of a particular function.
  • skin may be considered a tissue.
  • tissue refers to tissue or cells associated with an injury that has become infected with microorganisms, and in particular, microorganisms capable of forming a biofilm or tissue on which a biofilm has formed.
  • the term 'therapeutic means an agent utilized to treat, combat, ameliorate, prevent or improve an unwanted condi ⁇ on or disease of a patient.
  • ⁇ "therapeutically effective amount” or “effective amount” of a composition as used herein is a predetermined amount calculated to achieve the desired effect.
  • a “therapeutically effective amount” of a composition of the invention may achieve one or more of preventing formation of a biofilm, disrupting preformed biofilm and/or enabling contact of one or more therapeutic agents with the microorganism responsible for the biofilm or enabling augmentation of the state of the tissue underlying the biofilm so as to ameliorate the disease state.
  • a 'biofilm'' as used herein describes an aggregate of microorganisms that exhibit cooperative behavior such as, for example, secretion of a polymeric matrix that protects the microorganisms from attack by the host immune system.
  • biological is meant, a non-drug material that can be used to treat, enhance, or replace any tissue, organ, or function in an organism.
  • a “surface active agent” or “surfactant,” as used herein, may refer to a substance thai is capable of reducing the surface tension of a material.
  • Embodiments of the invention presented herein are generally directed to compositions for use in preventing the formation of biofilms and treating biofilms that have formed, methods for using such compositions and materials including such compositions such as, for example, wound dressings, surgical equipment and syringes.
  • Embodiments of the invention are directed to treating biofilms both living and non-living objects using the compositions of the invention.
  • Some embodiments are directed to compositions and methods useful for the treatment of a palienl, living tissue or biomaterial.
  • Compositions used in such embodiments may be referred to as "pharmaceutical compositions" which generally refers to a composition that is meant for application on or in a patient, living tissue or a biomaterial. Similar compositions, even those having the same makeup, may be useful in methods for treating biofilms on objects that are not living or utilized in the treatment of a living being which are also encompassed by the invention described herein.
  • the composition of the invention may at least include a surface active agent and a sub-lethal amount or dose of an antimicrobial agent.
  • Surface active agents are well known in the art, and suitable surface active agents for preparing the compositions of the invention are not particularly limiting.
  • anionic, cationic or non-ionic surface active agents may be used individually or in combination.
  • non-ionic surface active agents based on a polyol and including alkylene oxide units such as ethylene oxide and propylene oxide may be used.
  • Such non-ionic surface active agents include, but are not limited to.
  • the surface active agent may be a copolymer, such as, a poloxamer, meroxapol, and poloxamine.
  • Poloxamers are well known in the an and generally refer to a class of non-ionic di-block or tri-block copolymers having a central hydrophobic chain of polyoxypropylene flanked by hydrophilic chains of polyoxyethylene.
  • An exemplary tri-block poloxamer may be of general formula: ir[OCH 2 CH 2 ] a [OCH(CH3)CIi2jb[OCH 2 CH 2 ] c OH where a, b and c arc an integer and reflect the number of ethylene oxide and propylene oxide monomers in each block.
  • the length of each polymer block may vary and may provide poloxamers with different properties, and poloxamers are available in various grades.
  • poloxamers are named using three digits, the first two digits x 100 give the approximate molecular mass of the polyoxypropylene core and the last digit x 10 gives the percentage polyoxyethylene content in the poloxamer.
  • poloxamer 188 would be expected to contain a polyoxypropylene core of 1800 g/mol and a polyethylene content of approximately 80%.
  • Exemplary poloxamers useful in embodiments of the invention may include, but are not limited to, poloxamers 101, 105. 105 benzoate, 108, 122, 123, 124, 181, 182, 182 diben/.oate, 183, 184, 185, 188.. 212, 215, 217, 231 , 234, 235, 237, 238, 282 S 284, 288, 331 , 333, 334, 335, 338, 401, 402, 403 and 407.
  • Meroxapols are well known in the art and generally refer to a class of nonionic di-block or tri-block copolymers having a central hydrophilic chain of polyoxyethylene flanked by hydrophobic chains of polyoxypropylene.
  • An exemplary tri-block mcroxapol may be of general formula:
  • a, b and c are an integer and reflect the number of ethylene oxide, and propylene oxide monomers in each block.
  • the length of each polymer block may vary and may provide meroxapols with different properties. Meroxapols are available in various grades, and are named using the system described above for poloxamers. Examples of meroxapols useful in embodiments of the invention include, but are not limited to, meroxapols 105, 108, 171 , 172, 174, 178, 251 , 252, 254, 258, 31 1, 312 and 314.
  • Poloxamines arc well known in the art and generally refer to a class of nonionic tri-block copolymers having a central ethylene diamine flanked on either side by polyoxycthylene-polyoxypropylene block copolymers. Such compounds conform to general formula:
  • poloxamines useful in embodiments of the invention include, but arc not limited to poloxamines 304, 504, 701, 702, 704, 707, 901, 904, 908, 1101, 1102. 1 104, 1301, 1302, 1304, 1307, 150L 1502, 1504 and 1508.
  • the number average molecular weight (M n ) of surface active agents, and particularly copolymer surface active agents of embodiments may vary and may be, for example, from about 600 to about 20,000, in some embodiments from about 600 to about 10,000, and in other embodiments, from about 1 ,000 to about 9,000. In particular embodiments, the M n may be lrom about 5,000 to about 8,500.
  • the weight of hydrophobic groups may also vary and may be from about 45% to about 95% by weight of the copolymer.
  • the surface active agent of embodiments may be hydrated by mixing a suitable dry formulation of a surface active agent with a solvent such as, for example, water.
  • a suitable dry formulation of a surface active agent with a solvent such as, for example, water.
  • Surface active agents may be hydrated by any method known in the art.
  • a surface active agent including a copolymer e.g., a poloxamer
  • the ratio of surface active agent to solvent may vary among embodiments and may be, for example, about 0.01% to about 99.99% w/w, about 20% to about 90% vv/w, about 30% to about 80% w/w and about 40% to about 70% w/w.
  • the ratio of surface active agent to water may be 1 :1 or about 50% w/w.
  • Embodiments of the invention include the use of a surface active agent such as those described above to treat or eradicate a biofilm or planklonic biofilm forming microorganisms.
  • a composition including a surface active agent may be applied to a surface or wound where biofilm exists or where planktonic biofilm forming microorganism may be present and there is a high likelihood of a biofilm forming.
  • the composition may reduce or eliminate an existing biofilm or inhibit the growth of or eradicate biofilm forming microorganisms thereby reducing or eliminating the formation a biofilm.
  • Such compositions may be applied to a wound on a patient or applied to a surface, such as, an operating (able or surgical instruments with similar efficacy.
  • the surface active agent composition may further include one or more therapeutic agents (e.g., 2, 3, or 4 therapeutic agents may be added to a surface active agent).
  • a therapeutic agent may be added to a surface active agent after the surface active agent has been hydrated.
  • a dry surface active agent may be mixed with a dry therapeutic agent and the surface active agent may be hydrated following such mixing, fn other embodiments, a dry mixture of surface active agent and therapeutic agent may be prepared and stored for a period of time before the surface active agent is hydrated. Any therapeutic agent known in the art may be mixed with the surface active agent to prepare a composition encompassed by the invention.
  • useful therapeutic agents may include, but are not limited to, antimicrobials, steroids (e.g., hydrocortisone, triamcinolone), pain medications (e.g., aspirin, an NSAID, and a local anesthetic), anti-inflammatory agents, biological cells and biological agents of various types and combinations thereof.
  • steroids e.g., hydrocortisone, triamcinolone
  • pain medications e.g., aspirin, an NSAID, and a local anesthetic
  • anti-inflammatory agents e.g., aspirin, an NSAID, and a local anesthetic
  • the therapeutic agent may be an antimicrobial agent.
  • Antimicrobial agents are well known and utilized in the art and include antibacterial, antifungal, and antiviral agents.
  • Examples of antimicrobials useful in embodiments of the invention include, but are not limited to, silver sulfadiazine, nanocrystalline silver, ionic silver, nystatin, nystatin/triamcinolone, bacitracin, nitrofurazone, nitrofurantoin, polymyxins (e.g., colistin, surfactin, polymyxin E and polymyxin B), doxycycline, natural and synthetic antimicrobial peptides and combinations of agents.
  • silver sulfadiazine nanocrystalline silver, ionic silver, nystatin, nystatin/triamcinolone, bacitracin, nitrofurazone, nitrofurantoin, polymyxins (e.g., colistin, surfactin, polymyxin E and polymyx
  • Antimicrobials of embodiments may also include topical antimicrobials (i.e., antiseptics), for example, silver salts, iodine, benzalkonium chloride, alcohol, hydrogen peroxide, chlorhexidine, honey and the like.
  • topical antimicrobials i.e., antiseptics
  • silver salts i.e., silver salts, iodine, benzalkonium chloride, alcohol, hydrogen peroxide, chlorhexidine, honey and the like.
  • the polymer matrix formed between microorganisms forms a barrier to many antimicrobial agents. Therefore, treatment of biofilms and biofilm forming microorganisms generally requires one or more doses of an antimicrobial agent that is often several limes greater lhan the lethal dosage required to treat individual microorganisms that do not form biofilms or planktonic biofilm forming microorganisms. Moreover, it has been reported that sub-inhibitory concentrations of antimicrobial agents may induce biofilm formation (see, for example, Frank et al.
  • the lethal dosage for treatment of biofilm forming microorganisms may be significantly higher than the standard therapeutically effective amount determined for planktonic microorganisms (i.e., a lethal amount or a lethal dosage) typically, used by one of ordinary skill in the art or the amount approved by a regulatory agency (i.e., the FDA or its European counterpart).
  • the surface active agent used in the context of the compositions of the invention may penetrate and/or disrupt established biofilms by weakening or dispersing the polymer matrix or portions of the polymer matrix thereby diminishing or eliminating its function in providing resilience to the entrenched microorganisms.
  • the surface active agent may enable the therapeutic agent to access the microorganisms of the biofilm and/or the tissues/surfaces beneath the biofilm improving delivery of a therapeutic agent to the microorganisms and/or the injured tissues.
  • a "standard therapeutically effective amount” or a “standard therapeutic dose 5 ' which as used herein refers to an amount of an antimicrobial agent suggested by the manufacturer or approved for clinical use by regulatory agencies such as, for example, the Food and Drug Administration (the "FDA") which effects treatment of microorganisms in planktonic form.
  • FDA Food and Drug Administration
  • a “standard therapeutic amount” or “standard therapeutic dose” may also refer to an amount of an agent sufficient to reduce or eliminate planktonic microorganisms.
  • biofilms are generally not effected by antimicrobial agents provided at a standard therapeutic effective amount because biofilms are resistant to many antimicrobial agents. Therefore, a standard therapeutically effective amount may not represent a therapeutically effective amount of an antimicrobial agent when the antimicrobial agent is used to treat a biofilm.
  • a standard therapeutically effective amount of antimicrobial agent may be sufficient to effectively treat both planktonic biofilm forming microorganisms and preformed biofilms when the microbial agent is administered in combination with a surface active agent.
  • the amount of a microbial agent required to successfully treat biofilm forming microorganism when administered in combination with a surface active agent may be a ''sublethal" amount (i.e.. less than a standard therapeutically effective amount).
  • a sub-lethal dose or “sub-lethal amouni” refer to an amount of an antimicrobial agent that is less than the standard therapeutically effective amount.
  • a sub-lethal amount of an antimicrobial agent may effectively eradicate or inhibit the growth of biofilm forming microorganisms or pathogens, or inhibit biofilm formation or eradicate formed biol ⁇ lms.
  • a sub-lethal amount of an antimicrobial agent in .some embodiments may be from about 10% to greater than about 50% less than the standard therapeutically effective amount or 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% less than the standard therapeutically effective amount approved by a regulatory agency.
  • a sub-lethal amount may be greater than 50% less than the standard therapeutically effective amouni.
  • a sub-lethal may include 100% of the standard therapeutically effective amount when the composition is used to treat a biofilm.
  • a standard therapeutically effective amount of a silver sulfadiazine is about 1.0% by weight when used in an antimicrobial cream or gel.
  • the amount of silver sulfadiazine in the composition may be decreased below the standard therapeutically effective amount to, for example, less than 1.0% by weight.
  • a sub-lethal amount of silver sulfadiazine in some embodiments may be less than 0.95% by weight, less than 0.90% by weight, less than 0.85% by weight, less than 0.80% by weight, less than 0.75% by weight, less than 0.70% by weight, less than 0.65% by weight, less than 0.60% by weight or less than 0.55% by weight of the composition.
  • the amount of silver sulfadiazine may be less than 0.5% by weight of the composition.
  • a therapeutically effective amount may be 100% of a therapeutically effective amount or 1.0% by weight of the composition.
  • a standard therapeutic dose of Polymyxin B is about 10,000 units/gram in various compositions.
  • a "sub-lethal" dose or amount of Polymyxin B may be from about 1% to about 50% less than the about 10,000 units/gram standard therapeutic dose, or 9,900 units/gram to 5,000 units/gram, respectively.
  • a sub-lethal amount may be greater than 50% less than a standard therapeutic effective amouni, for example, about 60% less, about 70% less or about 80% less.
  • a therapeutically effective amount may be 100% of a therapeutically effective amount or 10,000 units/gram.
  • a standard therapeutic dose of nystatin is about 4,000 units/gram.
  • a "sub-lethal" dose of nystatin may be from about 1% less (3,960 units/gram) to about 50% less (2,000 units/gram).
  • a standard therapeutically effective amount of nitrofurantoin is about 0.3%. Therefore, a sub-lethal amount of nitrofurantoin may be less than about 0.3%, for example, about 0.29% to about-0.15%.
  • a therapeutically effective amount may be 100% of a therapeutically effective amount or 4,000 units/gram.
  • compositions of embodiments of the invention may be administered in combination with secondary active agents, such as, for example, drugs, adjuvants, protease inhibitors or other compatible drugs or compounds where such combination is seen to be desirable or advantageous in achieving the desired effects of the methods described herein.
  • the secondary active agent may be administered separately from the composition, and in others, the secondary active agent may be a component of the compositions of the invention.
  • the composition containing a surface active agent and a sub-lethal amount of an antimicrobial agent may further contain a drug for reducing irritation or enhancing healing such as, for example, an anti-inflammatory agent, anesthetic, pain killer or steroid.
  • compositions encompassed by the invention may include additives such as stabilizers, antioxidants, osmolality adjusting agents, buffers, pH adjusting agents, chelants, calcium chelate complexes, salts or combinations thereof.
  • a stabilizer such as appropriate pharmaceutical grade surfactants such as, TWEHN or saccharides, like dextrose, may be added to the compositions of the invention, and in some embodiments, such compositions may also include conventional pharmaceutical excipicnts and/or additives.
  • suitable pharmaceutical excipients may include stabilizers, antioxidants, osmolality adjusting agents, buffers, and pH adjusting agents
  • suitable additives may include physiologically biocompatible buffers (e.g., troraethamine hydrochloride), additions of chclanis (such as, for example, DTP ⁇ or DTPA-bisamide) or calcium chelate complexes (as for example calcium DTPA, CaNaDTPA-bisamide), or optionally, additions of calcium or sodium salts (for example, calcium chloride, calcium ascorbate, calcium gluconate or calcium lactate).
  • physiologically biocompatible buffers e.g., troraethamine hydrochloride
  • additions of chclanis such as, for example, DTP ⁇ or DTPA-bisamide
  • calcium chelate complexes as for example calcium DTPA, CaNaDTPA-bisamide
  • calcium or sodium salts for example, calcium chloride, calcium ascorbate, calcium gluconate or calcium lac
  • compositions may include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate and the like. For example, about 1 to about 95% by volume or, in a further example, 25% to about 75% by volume of any of the carriers and cxcipients listed above may be mixed into the compositions of the invention. Additional additives such as coloring agents, thickeners, lubricants and so on may also be added to the compositions of the invention.
  • Compositions of various embodiments of the invention may be prepared as described in Remington's Pharmaceutical Science, 17th cd., Mack Publishing Company, Easton, Pa. (1985), the entire disclosure of which is herein incorporated by reference, and such pharmaceutical compositions may be packaged for use as a liquid, gel. cream, solid, emulsion and dispersion.
  • Various embodiments of the invention also include methods for using the compositions described above.
  • some embodiments of the invention are directed to a method for treating a biofilrn including the step of contacting the biofilrn with a composition containing a surface active agent and a sub-lethal amount of an antimicrobial agent
  • other embodiments include a method for preventing a biofilm including the step of contacting biofilm forming microorganisms with a composition containing a surface active agent and a sub-lethal amount of an antimicrobial agent.
  • the biofilm may be present on a patient, for example, a human or a non-human animal, and in particular embodiments, the biofilm may be part of a wound.
  • the biofilm or biofilm forming microorganisms may be present on a biomatcrial that may contact a patient.
  • the biofilm or biofilm forming microorganisms may be present on tissue removed from a patient or tissue that is outside of the patient and may or may not be replaced back into the patient.
  • the invention also encompasses methods for using a composition including a surface active agent and a sub-lethal amount of a antimicrobial agent for treating surfaces. Therefore, the compositions of the invention may have non-pharmaceutical applications.
  • a composition including a surface active agent and a sub-lethal amount of an antimicrobial agent may by applied to an inanimate object, such as, but not limited to a chair, table, side board, machine or various parts of a machine or combinations thereof.
  • the compositions of the invention may be applied surgical instruments and/or surfaces of objects in an operating room.
  • the compositions of the invention may be applied to surfaces of devices meant to be implanted in a patient prior to implantation such as, a medical device, for example, a catheter.
  • contacting the biofilm or the biofilm forming microorganism may occur by any method known in the art.
  • the composition may be applied by hand or mechanically using, for example, extrusion or spray delivery.
  • the composition may be delivered by, for example, topical administration which may be performed by hand, mechanically (e.g., extrusion and spray delivery) or as a component in a dressing such as gauze or other wound coverings.
  • compositions of the invention are administered or applied directly to a tissue or biomaterial surface by hand or mechanically, it may be important to apply the composition so as to achieve a therapeutic coating.
  • a therapeutic coating generally refers io an amount of the composition which may form a substantially uniform covering over the effected area and may encompass non-effected areas surrounding an injury or wound.
  • the composition is delivered by hand, there can be considerable variation in the thickness of layers applied by practitioners.
  • a therapeutic coating may be applied or administered alone, and in other embodiments, a therapeutic coating may be applied in combination with an overlying dressing.
  • a uniform therapeutic coating may be achieved in a single administration or in several applications over the effected area, and a therapeutic coating delivered in this manner may be provided alone or in combination with an overlying dressing.
  • the thickness of a therapeutic coating of the composition when applied may vary in accordance with the size of a wound, the time available to apply the composition, the amount of composition available and other variables.
  • the thickness of the applied compositions may be from about 1 inch thick to less than about 1/10,000 inch thick or about 1 inch, about l /. inch, about 1 A inch or about 1/100 inch.
  • the thickness may vary in a single application.
  • the composition may be applied more thickly in the area of a wound and less thickly in the area surrounding the wound.
  • compositions may be applied to a wound that does not exhibit signs of biofilm formation while in still other embodiments, a greater amount of the composition may be applied to wounds that exhibit symptoms of biofilm formation.
  • a wound and the area surrounding the wound may be covered with a medical fabric such as, for example, band-aids or gauze, after being contacted with the composition.
  • the methods described above may be useful for treating patients exhibiting a number of indications or suffering from any number of conditions that may be susceptible to microbial biofilm formation or may already have a biofilm present. Such patients may be considered "in need of treatment.
  • the indications or conditions that may include risk of biofilm formation and may require treatment using the compositions of the invention may arise from, for example, injury in which skin and/or skin function is disrupted or surgery. Examples of such injuries may include, but arc not limited to burns, abrasions, cuts, scrapes, and other denuding tissue injuries or combinations of these.
  • the compositions of the invention may be used to treat chronic wounds.
  • chronic wounds are characterized by non-healing skin wounds and include, for example, chronic venous ulcers, diabetic ulcers, arterial ulcers, pressure ulcers (e.g., decubitis ulcers), radiation ulcers, traumatic wounds, open, complicated non-healing wounds and the like.
  • Still other embodiments of the invention include methods for treating or preventing a microbial biofilm including the steps of: administering a first composition containing a surface active agent and that does not contain an antimicrobial agent; and administering a second composition that contains a surface active agent and a sub-lethal amount of an antimicrobial agent.
  • the second composition may generally be administered after the first composition.
  • the first composition may be applied and the second composition may be applied without any intervening steps, and in other embodiments, the first composition may be applied and then removed or partially removed by, for example, being wiped away prior to administration of the second composition, prior to administration of the second composition.
  • the method may further include the step of applying a dressing or covering to the treated surface following administration of cither the first or second or both compositions.
  • the second composition may be included in the dressing material.
  • the second composition may be impregnated in a dressing material or otherwise contained or encompassed by the dressing material.
  • the dressing including the second composition may be applied over a surface to which the first composition has been administered.
  • the second composition may be applied directly to a dressing material by, for example, coating a surface of the dressing material with the second composition, prior to applying the dressing to the surface treated with the first composition.
  • the time between the first administration and the second administration may vary throughout embodiments and may be based on the patient and practitioner.
  • the time between administration of the first and second compositions may be from a partial second (e.g., 0.001 seconds) up to several minutes (e.g., 1, 2, 3, 4, 5, 10, 15, 20, 25 or 30 or greater than 30 minutes) or several hours (e.g., 1 , 2, 3, 4 or 5 or greater than 5 hours).
  • a dressing for treating or preventing a microbial biofilm that includes: a first layer including a composition containing a surface active agent and no antimicrobial agent; a second layer including a second composition containing a surface active agent and a sub-lethal amount of an antimicrobial agent; and a dressing material supporting the first and second composition layers.
  • the second layer is located between the first layer and the dressing material.
  • the second layer may form a coating covering a surface of the dressing material, and in other embodiments, the second layer is impregnated or otherwise contained within or encompassed by the dressing material.
  • the first and second composition layers may completely encompass the dressing, and in others, the first and/or second composition layers may be placed such that the compositions may be positioned to be delivered to only a portion of the patient to which the dressing is applied.
  • the entire dressing includes the first and second composition layers, and in another embodiment, the dressing may include a middle section that includes first and second composition layers that is flanked on either side by portions of the dressing that do not contain composition layers.
  • the entire dressing may contain a first composition layer and a portion of the dressing may contain the second composition layer.
  • the dressing may further include a spacer layer between the first and second composition layers.
  • the spacer layer may be a dressing material that allows the antimicrobial agent to be brought into contact with the patient after the dressing has been applied to the patient.
  • the spacer layer may be a pharmaceutical agent such as, for example, a polymer, a cream, a wax and the like that may separate the first and second compositions.
  • the spacer layer may lose its integrity by, for example, disintegrating, dissipating, becoming porous, etc., upon application of the dressing to a patient.
  • the spacer layer may degrade as it is warmed to body temperature. In general as the spacer layer loses integrity means, it may no longer function as a barrier between the first and second composition.
  • the second composition may come into contact with patient and/or the first composition as the spacer layer loses integrity.
  • the dressing material of embodiment may be any pharmaceutically acceptable fabric.
  • the dressing material may be gauze, a gauze pad, polymeric or natural liber band-aid, second skin or any other type of material or fabric useful in the medical arts to cover a wound or at least keep a therapeutic agent or pharmaceutical composition in contact with a patient.
  • compositions of the invention may be packaged in any way which allows a practitioner or an injured individual access to the composition following injury.
  • the first and/or second compositions are contained within a tube or bottle from which the composition may be poured and applied to the injury, and in another embodiment, the first and/or second composition may be absorbed onto a swab which may be used to apply the compositions of the invention.
  • the first and/or second composition may be contained within a vial that is broken to release the composition which may then be applied by means discussed herein above.
  • other packaging means are available and may be used in conjunction with embodiments of the invention.
  • compositions of the invention may eliminate the biofilm forming microorganisms before biofilm formation has if the composition is applied to a wound prior to formation of a biofilm.
  • biofilm forming microorganisms begin to form a biofilm only when a population of planktonic microorganisms reach a specific cell density and/or when the concentration of microorganism produced autoinducer has reached a threshold level.
  • the concentration of autoinducer and cell density requirements may vary among b ⁇ ofilm forming species.
  • application of the compositions of the invention prior to formation of a biofilm may reduce the microorganism population such that planklonic microorganisms may not reach an adequate cell density to form a biofilm thereby inhibiting biofilm formation.
  • the present invention provides a method for treating a wounded patient by administering to the wounded patient a composition containing a surface active agent and a sub-lethal amount of an antimicrobial agent within about 10 hours of injury.
  • the wound may be treated within less than 10 hours.
  • a wound may be treated within 8 hours, 5 hours, 4, hours, 3 hours, 2 hours or 1 hour or within 30 minutes, within 10 minutes or within 5 minutes.
  • treating an injury within about 2 hours or less may ensure that the wound is treated while the biofilm forming pathogens in the wound are in a planktonic state or before biofilm forming pathogens have invaded the wound.
  • any biofilm forming pathogens are contacted by the composition of the invention before the concentration of autoinducer has reached a threshold level to induce biofilm formation and/or before the cell density of the pathogen has reached a similar threshold level. Accordingly, formation of a biofilm may be reduced or eliminated, and the wound may be more easily treated.
  • compositions prepared in accordance with embodiments of the invention were evaluated for efficacy using 'The Calgary Biofilm Device" as described in Ceri et al. "The Calgary Device: New Technology for the Rapid Determination of Antibiotic Susceptibilities of Bacterial Biofilms.” J. Clin. Microbio. 1999; 37: 1771-1776 hereby incorporated by reference in its entirety. Briefly, this simple assay allows microorganisms to grow on pins which are positioned on the Hd of a 96 well microtiier plate and which protrude into the wells of the 96 well microliter plate when the Hd is positioned on the plate.
  • Biofilm forming microorganisms are placed on the pins and contact growth media and/or test compounds in the wells of a microliter plate. This allows rapid analysis of test compounds efficacy against biofilm forming microorganisms.
  • the data resulting from the assay produces both MlC and MBEC values by observing biofilm growing on the pegs. Similar assays may also be used to determine the MlC and MBEC of pianktonic microorganisms by growing the microorganisms suspended in the wells of a 96 well microliter plate, and observing the growth of the microorganisms in wells that contain the test compound and comparing these values with control well that do not contain a test compound.
  • Poloxamer 188 dissolved in water to concentrations of 45%, 50% and 55% by volume poloxamcr 188.
  • PSSD 50% poloxamer 188 and 1% silver sulfadiazine in water
  • 50% poloxamer 188 in ' water concentrations of 90%, 80%, 70%, 60% and 50% by volume PSSD.
  • PT ⁇ G 50% poloxamer 188 and TAG (Polymyxin B [10,000 U/g], nitrofurantoin [0.3%], nystatin [4,000 U/gJ) in water) at 100% and diluted with 50% poloxamer 188 in water to concentrations of 90%, 80%, 70%, 60% and 50% by volume PTAG.
  • SSD cream 1% silver sulfadiazine al 100% and diluted in cream to concentrations of 90%, 80%, 70%, 60% and 50% by volume SSD.
  • ⁇ n inoculum of the microorganism to be tested was prepared to match a 0.5 McFarland Standard (1.5 x 10 8 cells per ml)in 3 ml of sterile water in a glass test tube using a sterile cotton swab. This inoculum was then diluted 1 in 30 in Cation Adjusted Mueller Hinton Broth (CAMHB) and inverted 3-5 times to achieve uniform mixing of the microorganism. A sample (lOO ⁇ l) of the diluted inoculum was serially diluting and spot plating on TSA to confirm the cell density of the sample.
  • CAMHB Cation Adjusted Mueller Hinton Broth
  • a contact plate is a sterile 96-well microtiter plate whose wells contain a concentration of the test composition as specified above.
  • a inoculum as described above were prepared, diluted 1 in 30 in Cation Adjusted Mueller Hinton Broth (C ⁇ MHB), inverted 3-5 times to achieve uniform mixing of the microorganism and sample (lOO ⁇ l) of the diluted inoculum was serially diluting and spot plating on ISA to confirm the cell density of the sample.
  • a challenge plate was prepared as described above, and 20 ⁇ l of the inoculum was added to each well of the challenge plate.
  • a sterile lid having 96 pegs corresponding to each of the wells of the challenge plate was placed over the challenge plate and the device was incubated in a humidified incubator at 37 0 C for 24 hours shaking at 110 revolutions per minute to allow biofilm on the peg for a specified contact time.
  • the minimum bactericidal concentration (MBC) value represents the lowest concentration which kills 99.9% of the population. Results were determined following the 24 hour incubation from the Test panels using the plate reader. To determine MBC, the optical density of the wells of each challenge plate was determined at 630 nm (OD ⁇ o)- Clear wells (OD 630 ⁇ 0.1) are evidence of inhibition and denoted (-). Wells in which bacterial growth is evident (OU63o greater than 0.1) are denoted with a plus (+).
  • MBEC Die minimum biofilm eradication concentration

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Abstract

La présente invention se rapporte à des compositions contenant un agent de surface actif ainsi qu'une quantité non mortelle d'un agent antimicrobien. L'invention se rapporte également à des procédés d'utilisation de ces compositions.
EP08730165A 2007-02-19 2008-02-19 Compositions pour traiter des biofilms, et procédés pour leur utilisation Ceased EP2120561A4 (fr)

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US11730168B2 (en) 2017-10-16 2023-08-22 Matoke Holdings Limited Antimicrobial superabsorbent compositions

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US9884136B2 (en) 2018-02-06
US9283278B2 (en) 2016-03-15
EP2120561A4 (fr) 2012-11-21
WO2008103673A1 (fr) 2008-08-28
AU2008218746A1 (en) 2008-08-28
US8871248B2 (en) 2014-10-28
EP3170396A1 (fr) 2017-05-24
AU2008218746B2 (en) 2014-03-13
US20130101661A1 (en) 2013-04-25
US20150099009A1 (en) 2015-04-09
US9603966B2 (en) 2017-03-28
US20190008993A1 (en) 2019-01-10
US20170216480A1 (en) 2017-08-03
US20160151533A1 (en) 2016-06-02
CA2678873C (fr) 2016-10-25
CA2678873A1 (fr) 2008-08-28
US20090202615A1 (en) 2009-08-13

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